Project Summary Every year, over a million children HIV-exposed but uninfected (CHEU) are born in sub-Saharan Africa and this population will continue to increase with improving availability of antiretroviral therapy (ART). The long-term effects of in utero exposure to HIV and ART on child health and well-being have not been adequately characterized, especially in resource-limited settings. CHEU are at higher risk for infectious diseases and recent studies suggest they may have impaired neurocognitive development compared to their children without HIV exposure. Identifying the causes of and risk factors for neurocognitive delay is essential for the development of effective interventions to improve the lives of CHEU children. This proposal takes advantage of the unique opportunity to evaluate the impact of in utero HIV and ART exposure on neurocognitive development in children by extending the cohort enrolled in an ongoing clinical study we are conducting in Malawi. We are screening pregnant women, enrolling infants and conducting intensive analysis of neonatal adaptive immunity among infants in three categories: (1) CHEU born to women diagnosed with HIV at the first antenatal visit, thus exposed to uncontrolled viremia for at least half of gestation; (2) CHEU born to women initiated on ART prior to conception with undetectable viral loads; and (3) infants born to HIV uninfected mothers. In this proposal, we will continue enrollment into our cohort of CHEU and children without HIV exposure to reach the sample size required to conduct a robust longitudinal analysis of neurocognitive outcomes. We will adapt standardized and locally validated assessment tools to investigate overall neurodevelopment as well as key neurocognitive domains. After our initial milestones are achieved, we propose to evaluate neurocognitive development at 18, 36, and 60 months of age. Our interdisciplinary study team of infectious disease specialists, developmental pediatricians, psychologists and immunologists will lead one of the most comprehensive studies of CHEU in resource-limited settings to simultaneously address the impact of maternal and neonatal factors on neurocognitive development on this population. We hypothesize that in utero exposure to HIV will impair neurocognitive development in the first five years of life and children born to HIV-infected mothers with untreated HIV infection at the start of pregnancy will demonstrate more delay than children of mothers with undetectable HIV viral load throughout pregnancy. We further hypothesize that immunological status at birth will contribute to impaired neurocognitive development in HEU children and explore the possibility that basic maternal history or laboratory tests may identify the highest risk infants. The results of this study can immediately be translated into interventions to improve the lives of CHEU, especially in low-resource settings.